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Bio marker introduction

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Sravan Thumati
Sravan Thumati

The document discusses biomarkers for several diseases. A biomarker is defined as an objectively measured indicator of biological or pathogenic processes. An ideal biomarker for diagnosis should have high sensitivity and specificity for a disease. Biomarkers can be used for screening, diagnosis, monitoring disease progression, and predicting outcomes or treatment responses. Examples of biomarkers discussed include procalcitonin for sepsis, rapid diagnostic tests detecting malaria antigens, ADA for tuberculosis pleural effusion, and CSF tau and amyloid beta for Alzheimer's disease diagnosis. Validation of biomarkers includes assessing accuracy, precision, limits of detection, and specificity.

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MEDICIN E UNIT 1
Introduction 2 Definition: The US FDA (2001)defines a biomarker as a characteristic i.e. objectively measured & evaluated as an indicator of normal biologic, pathogenic or pharmacologic responses to therapeutic intervention.
WHO (2010) Biomarkers includes- Almost any measurement reflecting an interaction between a biological system and a potential hazard, which may be chemical, physical, or biological; The measured response may be functional and physiological, biochemical at the cellular level or a molecular interaction. Ex : Pulse and blood pressure through basic chemistries to more complex laboratory tests of blood and other tissues.
Ideal biomarker 4
Ideal biomarker
Bio marker introduction
Biomarker & Diagnosis Ideal Marker for diagnosis Should have great sensitivity (>0.9), specificity (>0.9), and accuracy in reflecting total disease burden. A tumor marker should also be prognostic of outcome and treatment. Samples for biomarker detection Blood, urine, or other body fluids samples Tissue samples.
Biomarker for Screening The marker must be highly specific, minimize false positive and negative The marker must be able to clearly reflect the different stages of the disease (early) The marker must be easily detected without complicated medical procedures. The disease markers released to serum and urine are good targets for application of early screening. The method for screening should be cost effective.
Biomarker Detection of biomarker diagnosis Self properties, e.g enzymatic activities, Antibodies, IHC, ELISA. Detection of biomarker Quantitative a link between quantity of the marker and disease Qualitative a link between exist of a marker and disease.
Quantitative Approaches Stable Isotope Labeling methods adds heavy isotopes to one sample so chemically identical compounds are mass shifted added to the peptides/proteins using reactive groups added to the proteins in vivo using heavy amino acids can be multiplexed Label free methods extracted ion chromatograms spectral counting
Validation of Biomaker Accuracy (agreement with a reference) Precision (repeatability, reproducibility) Limit of Detection (sensitivity) Interference, Cross-reactivity (specificity) Sample preparation / conditions Performance around the cut-off Potential for carryover, cross-hybridization.
Biomarker Uses Diagnosis, in symptomatic patients Early detection (screening), enabling intervention at an earlier and potentially more curable stage than under usual clinical diagnostic conditions Monitoring of disease response during therapy, with potential for adjusting level of intervention (e.g. dose) on a dynamic and personal basis Risk assessment, leading to preventive interventions for those at sufficient risk Prognosis, allowing for more (less) aggressive therapy for patients with worse (better) prognosis Prediction. E.g., predicts safety, efficacy (PK/PD) of a specific therapy, thereby providing guidance in selecting it for patients or tailoring its dose. Last three are attempts to predict the future.
Advantages Disadvantages Objective assessment Timing is critical Precision of measurement Expensive (cost for analysis) Reliable; validity can be established Storage (longevity of samples) Less biased than questionnaires Laboratory errors Disease mechanisms often studied Normal range difficult to establish Homogeneity of risk or disease Ethical responsibility Biomarker
Biomarkers in Sepsis
Ideal biomarker for sepsis Sensitive and specific for bacterial infection . Single reliable cut-off value. Unaffected by acute illness or chronic disease. Level correlates with severity and mortality. Short half-life. Inexpensive and timely result (<1hr). Ex . Procalcitonin ,CRP,aptt,TNF, IL
The potential role of biomarkers for diagnosis remains undefined. Recomendation Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection (grade 2C). International Guidelines for Management of Severe Sepsis and Septic Shock: 2013
Biomarkers in malaria
Malaria diagnosis serological biomarker Rapid detection tests (RDTs) - immunochromatography assay. Plasmodial lactate dehydrogenase (pLDH). Histidine-rich protein II (HRP II). Published sensitivities of RDTs for P. falciparum range from comparable to those of good field microscopy (> 90% at 100500 parasites/亮l of blood) to very poor (40 50%) for some widely used products. Priyamvada Jain et al; Potential Biomarkers and Their Applications for Rapid and Reliable Detection of Malaria. 852645, 2014, 1-20. The use of rapid diagnostic tests. Geneva, Roll Back Malaria, WHO Regional Office for the Western Pacific and UNDP/World Bank/WHO/UNICEF Special Programme for Research
WHO maintains a list of RDT manufacturers with ISO 13485:2003 certification. Advantages Rapid diagnosis. Fewer requirement of trained and skilled personal. Disadvantages Unpredictable sensitivity. Inability to differentiate between new infection and recently treated infection as few antibodies (HRP2) persist for 2 to 3 weeks.
Bio marker introduction
Biomarkers in TB
TB pleural effusion (ADA) Diagnosis of TB pleural effusion is a challenging task. None of the diagnostic modalities available till date are able to diagnose TB pleural effusion as So ADA is being used as a biomarker in diagnosing TB pleural effusion . It is a quantitative biomarker produced from T Lymphocytes .
Bio marker introduction
Bio marker introduction
Bio marker introduction
LAM Detection of the Mycobacterium tuberculosis cell wall antigen lipoarabinomannan (LAM) in urine permits diagnoses of tuberculosis (TB). This can be achieved at the point-of-care within just 30 minutes using the Determine TB-LAM, which is a commercially available, lateral-flow urine strip test assay. Currently this test is validated in africa in HIV positive patients . Sensitivity and specificity are low in compared to the Xpert MTB/RIF assay.
Advantages simplicity of use, lack of instrumentation, speed of use with results available after 25 minutes Low cost (initially marketed at $3.50 per test) Implemented at the point-of-care. This is currently used in patients enrolled for ART treatment as a rapid test to rule out dissemenated TB.
CSF (Cerebrospinal fluid) Total tau T-tau increase (sensitivity- 95% & specificity- 84%). CSF Phosphorylated tau P-tau - increase (sensitivity- 95% & specificity- 83%). CSF A硫 A硫42 decrease (sensitivity- 95% & specificity- 82%). Magnetic resonance imaging MRI (functional scan using FDG 18 Glucose ) atrophy of Hippocampus (sensitivity 88% & specificity 91%). SPECT scanning (63% sensitivity and an 87% specificity). K. Blennow et al. Fluid Biomarkers in Alzheimer Disease, Cold Spring Harb Perspect Med, Apr 2012;2:006221. J Cummings et al. Biomarker-Driven Therapeutic Management of Alzheimers Disease: Establishing the
CSF Amyloid 硫 and tau. Neuromelanin antibodies. PET biomarkers include [18F]-DOPA for estimating dopaminergic neurotransmission. Reduced brain regional N-acetyl-aspartate using magnetic resonance spectroscopy. 留-Synculein index & Charnoly body.
Bio marker introduction

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Bio marker introduction

  • 2. Introduction 2 Definition: The US FDA (2001)defines a biomarker as a characteristic i.e. objectively measured & evaluated as an indicator of normal biologic, pathogenic or pharmacologic responses to therapeutic intervention.
  • 3. WHO (2010) Biomarkers includes- Almost any measurement reflecting an interaction between a biological system and a potential hazard, which may be chemical, physical, or biological; The measured response may be functional and physiological, biochemical at the cellular level or a molecular interaction. Ex : Pulse and blood pressure through basic chemistries to more complex laboratory tests of blood and other tissues.
  • 7. Biomarker & Diagnosis Ideal Marker for diagnosis Should have great sensitivity (>0.9), specificity (>0.9), and accuracy in reflecting total disease burden. A tumor marker should also be prognostic of outcome and treatment. Samples for biomarker detection Blood, urine, or other body fluids samples Tissue samples.
  • 8. Biomarker for Screening The marker must be highly specific, minimize false positive and negative The marker must be able to clearly reflect the different stages of the disease (early) The marker must be easily detected without complicated medical procedures. The disease markers released to serum and urine are good targets for application of early screening. The method for screening should be cost effective.
  • 9. Biomarker Detection of biomarker diagnosis Self properties, e.g enzymatic activities, Antibodies, IHC, ELISA. Detection of biomarker Quantitative a link between quantity of the marker and disease Qualitative a link between exist of a marker and disease.
  • 10. Quantitative Approaches Stable Isotope Labeling methods adds heavy isotopes to one sample so chemically identical compounds are mass shifted added to the peptides/proteins using reactive groups added to the proteins in vivo using heavy amino acids can be multiplexed Label free methods extracted ion chromatograms spectral counting
  • 11. Validation of Biomaker Accuracy (agreement with a reference) Precision (repeatability, reproducibility) Limit of Detection (sensitivity) Interference, Cross-reactivity (specificity) Sample preparation / conditions Performance around the cut-off Potential for carryover, cross-hybridization.
  • 12. Biomarker Uses Diagnosis, in symptomatic patients Early detection (screening), enabling intervention at an earlier and potentially more curable stage than under usual clinical diagnostic conditions Monitoring of disease response during therapy, with potential for adjusting level of intervention (e.g. dose) on a dynamic and personal basis Risk assessment, leading to preventive interventions for those at sufficient risk Prognosis, allowing for more (less) aggressive therapy for patients with worse (better) prognosis Prediction. E.g., predicts safety, efficacy (PK/PD) of a specific therapy, thereby providing guidance in selecting it for patients or tailoring its dose. Last three are attempts to predict the future.
  • 13. Advantages Disadvantages Objective assessment Timing is critical Precision of measurement Expensive (cost for analysis) Reliable; validity can be established Storage (longevity of samples) Less biased than questionnaires Laboratory errors Disease mechanisms often studied Normal range difficult to establish Homogeneity of risk or disease Ethical responsibility Biomarker
  • 15. Ideal biomarker for sepsis Sensitive and specific for bacterial infection . Single reliable cut-off value. Unaffected by acute illness or chronic disease. Level correlates with severity and mortality. Short half-life. Inexpensive and timely result (<1hr). Ex . Procalcitonin ,CRP,aptt,TNF, IL
  • 16. The potential role of biomarkers for diagnosis remains undefined. Recomendation Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection (grade 2C). International Guidelines for Management of Severe Sepsis and Septic Shock: 2013
  • 18. Malaria diagnosis serological biomarker Rapid detection tests (RDTs) - immunochromatography assay. Plasmodial lactate dehydrogenase (pLDH). Histidine-rich protein II (HRP II). Published sensitivities of RDTs for P. falciparum range from comparable to those of good field microscopy (> 90% at 100500 parasites/亮l of blood) to very poor (40 50%) for some widely used products. Priyamvada Jain et al; Potential Biomarkers and Their Applications for Rapid and Reliable Detection of Malaria. 852645, 2014, 1-20. The use of rapid diagnostic tests. Geneva, Roll Back Malaria, WHO Regional Office for the Western Pacific and UNDP/World Bank/WHO/UNICEF Special Programme for Research
  • 19. WHO maintains a list of RDT manufacturers with ISO 13485:2003 certification. Advantages Rapid diagnosis. Fewer requirement of trained and skilled personal. Disadvantages Unpredictable sensitivity. Inability to differentiate between new infection and recently treated infection as few antibodies (HRP2) persist for 2 to 3 weeks.
  • 22. TB pleural effusion (ADA) Diagnosis of TB pleural effusion is a challenging task. None of the diagnostic modalities available till date are able to diagnose TB pleural effusion as So ADA is being used as a biomarker in diagnosing TB pleural effusion . It is a quantitative biomarker produced from T Lymphocytes .
  • 26. LAM Detection of the Mycobacterium tuberculosis cell wall antigen lipoarabinomannan (LAM) in urine permits diagnoses of tuberculosis (TB). This can be achieved at the point-of-care within just 30 minutes using the Determine TB-LAM, which is a commercially available, lateral-flow urine strip test assay. Currently this test is validated in africa in HIV positive patients . Sensitivity and specificity are low in compared to the Xpert MTB/RIF assay.
  • 27. Advantages simplicity of use, lack of instrumentation, speed of use with results available after 25 minutes Low cost (initially marketed at $3.50 per test) Implemented at the point-of-care. This is currently used in patients enrolled for ART treatment as a rapid test to rule out dissemenated TB.
  • 28. CSF (Cerebrospinal fluid) Total tau T-tau increase (sensitivity- 95% & specificity- 84%). CSF Phosphorylated tau P-tau - increase (sensitivity- 95% & specificity- 83%). CSF A硫 A硫42 decrease (sensitivity- 95% & specificity- 82%). Magnetic resonance imaging MRI (functional scan using FDG 18 Glucose ) atrophy of Hippocampus (sensitivity 88% & specificity 91%). SPECT scanning (63% sensitivity and an 87% specificity). K. Blennow et al. Fluid Biomarkers in Alzheimer Disease, Cold Spring Harb Perspect Med, Apr 2012;2:006221. J Cummings et al. Biomarker-Driven Therapeutic Management of Alzheimers Disease: Establishing the
  • 29. CSF Amyloid 硫 and tau. Neuromelanin antibodies. PET biomarkers include [18F]-DOPA for estimating dopaminergic neurotransmission. Reduced brain regional N-acetyl-aspartate using magnetic resonance spectroscopy. 留-Synculein index & Charnoly body.

Editor's Notes

  1. The utility of procalcitonin levels or other biomarkers (such as CRP) to discriminate the acute inflammatory pattern of sepsis from other causes of generalized inflammation (eg, postoperative, other forms of shock) has not been demonstrated
  2. Currently who recomends use of